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D. Yang et al. / Bioorg. Med. Chem. 8 (2000) 321±327
treated overnight with potassium carbonate (0.5 g,
3.6 mmol) and 1,5-dibromopentane (0.23 g, 5 mmol).
After re¯uxing for 96 h, the solution was evaporated
and then treated with water and extracted several times
with dichloromethane. After washing with brine, the
organic phase was dried over Na2SO4, ®ltered and eva-
porated. The resulting product was puri®ed by ¯ash
chromatography (CH2Cl2/methanol, 95/5), treated with
a solution of HCl in ethyl acetate and recrystallized
in ethanol/ethyl acetate to give 0.085 g (yield: 22%)
of trans-3c hydrochloride, mp >200ꢀC. 1H NMR
()-(cis)-4-Amino-N-(2-benzylamino-1-cyclopropyl)-5-
chloro-2-methoxybenzamide (cis-3d). Following the pro-
cedure described for trans-3d, benzamide cis-3a (0.6 g,
2 mmol) gave 0.4 g (yield: 56%) of cis-3d, mp 140 ꢀC. 1H
NMR (CDCl3) d 8.2 (m, 1H, NH), 8.1 (s, 1H, HCCCl),
7.3 (m, 5H, Har), 6.3 (s, 1H, HCCOCH3), 4.4 (m, 2H,
NH2), 3.9 (s, 2H, CH2NH), 3.8 (s, 3H, OCH3), 3.3 (m,
1H, CHNHCO), 2.4 (m, 1H, CHNHCH2), 1.0 (m, 1H,
CH2trans), 0.4 (m, 1H, CH2cis). Anal. calcd for C18H20
ClN3O2.1/2H2O: C, 60.93; H, 5.97; N, 11.84. Found: C,
60.90; H, 5.95; N, 11.75.
(CD3OD)
d 7.8 (s, 1H, HCCCl), 6.5 (s, 1H,
HCCOCH3), 3.9 (s, 3H, OCH3), 3.2 (m, 4H, NCH2), 3.1
(m, 1H, CHNHCO), 2.5 (m, 1H, CHN), 1.8 (m, 4H,
NCH2CH2), 1.6 (m, 2H, NCH2CH2CH2), 1.3 (m, 2H,
CH2); 13C NMR (CD3OD) d 169 (CONH), 160 (Car
OCH3), 151 (CarNH2), 133 (CarHCCl), 111 (CarCl and
CarCONH), 99 (CarHCOCH3), 57 (OCH3), 55 (NCH2),
47 (NCH), 30 (CHNHCO), 25, 24 and 13 (CH2). Anal.
calcd for C16H22ClN3O2.HCl.H2O: C, 50.79; H, 6.61; N,
11.11. Found: C, 50.76; H, 6.5; N, 11.35.
()-(trans)-4-Amino-5-chloro-2-methoxy-N-{2-[N0,N0-bis-
(phenylmethyl)amino]-1-cyclopropyl}benzamide (trans-
3e). A solution of trans-3a (0.5 g, 1.7 mmol) in DMF
(5 mL) was treated overnight with potassium carbonate
(0.3 g, 2.16 mmol), benzyl chloride (0.25 g, 2 mmol) and
potassium iodide (0.01 g). After re¯uxing for 96 h, the
solution was evaporated and then treated with water
and extracted with ethyl acetate. After washing with
brine, the organic phase was dried over MgSO4, ®ltered
and evaporated to give 0.44 g (yield: 59%) of trans-3e,
mp 154 C. H NMR (CDCl3) d 8.1 (s, 1H, HCCCl),
7.6 (m, 1H, NH), 7.3 (m, 10H, Har), 6.3 (s, 1H,
HCCOCH3), 4.4 (m, 2H, NH2), 3.8 (s, 3H, OCH3),
3.7,(4H, CH2N), 2.8 (m, 1H, CHNH), 2.0 (m, 1H,
CHN), 1.0 and 0.7 (m, 2H, CH2). Anal. calcd for
C25H26ClN3O2: C, 68.12; H, 6.19; N, 9.41. Found: C,
68.5; H, 6.01; N, 9.64.
ꢀ
1
()-(cis)-4-Amino-N-[2-(1-piperidine)-1-cyclopropyl]-5-
chloro-2-methoxy benzamide (cis-3c). Following the
procedure described for trans-3c, cis-3a (0.2 g,
0.54mmol) gave 0.12g (yield: 53%) of cis-3c 2-methoxy-
benzamide which was isolated as oxalate (MeOH/di-
1
ethyl ether). H NMR (CDCl3) d 7.8 (s, 1H, HCCCl),
6.5 (s, 1H, HCCOCH3), 3.9 (s, 3H, OCH3), 3.2 (m, 4H,
NCH2), 3.1 (m, 1H, CHNHCO), 2.8 (m, 1H, CHN), 1.8
(m, 4H, NCH2 CH2), 1.7 (m, 2H, NCH2CH2CH2), 1.3
(m, 2H, CH2); 13C NMR (CD3OD) d 169 (CONH), 160
(CarOCH3), 151 (CarNH2), 133 (CarHCCl), 111 (CarCl
and Car CONH), 98 (CarHCOCH3), 57 (OCH3), 56
(NCH2), 43 (NCH), 29 (CHNHCO), 24, 23 and 10 (CH2).
Anal. calcd for C16H22ClN3O2.2C2H2O4: C, 47.66; H,
5.16; N, 8.34. Found: C, 48.01; H, 4.85; N, 8.12.
()-(trans)-4-Amino-N-[2-(N-benzyl-N-methylamino)-1-
cyclopropyl]-5-chloro-2-methoxybenzamide
(trans-3f).
Following the procedure described for 3d, benzamide
trans-3d (0.4 g, 2 mmol) and 0.15 mL (2 mmol) of form-
aldehyde (37% in methanol) gave 0.2 g (yield: 48%) of
ꢀ
1
trans-3f, mp 137 C. H NMR (CDCl3) d 8.1 (s, 1H,
HCCCl), 7.6 (m, 1H, NH), 7.3 (m, 5H, Har), 6.3 (s, 1H,
HCCOCH3), 4.5 (m, 2H, NH2), 4.0±3.6 (m, 2H, CH2N),
3.8 (s, 3H, OCH3), 2.9 (m, 1H, CHNH), 2.3 (s, 3H,
NCH3), 1.9 (m, 1H, CHN), 1.0 and 0.8 (m, 2H, CH2).
Anal. calcd for C19H22ClN3O2: C, 63.42; H, 6.16; N,
11.68. Found: C, 63.75; H, 6.33; N, 11.51.
()-(trans)-4-Amino-N-(2-benzylamino-1-cyclopropyl)-
5-chloro-2-methoxybenzamide (trans-3d). Benzaldehyde
(0.48 g, 4.5 mmol) in methanol (10 mL) was added
dropwise to a solution of trans-3a (0.72 g, 2.5 mmol) in
methanol (40 mL) at 0 ꢀC. After 15 min, sodium cyano-
borohydride (0.47 g, 7.5 mmol) were added and the
solution was allowed to warm to room temperature for
1 h with a limited addition of acetic acid to keep the pH
at 7. After evaporation, the solution was extracted with
water and then diethyl ether. The organic phase was
extracted with brine, dried over Na2SO4, ®ltered and
then evaporated. Puri®cation of the residue by ¯ash
chromatography (CH2Cl2/methanol/NH4OH, 90:9:1)
gave 0.4 g (yield: 46%) of trans-3d, mp 130 ꢀC. 1H NMR
(CDCl3) d 8.1 (s, 1H, HCCCl), 7.6 (m, 1H, NH), 7.3 (m,
5H, Har), 6.3 (s, 1H, HCCOCH3), 4.6 (m, 2H, NH2), 3.9
(s, 2H, CH2NH), 3.8 (s, 3H, OCH3), 2.8 (m, 1H,
CHNHCO), 2.5 (m, 1H, NH), 2.2 (m, 1H, CHNHCH2),
1.0 and 0.7 (m, 2H, CH2); 13C NMR (CDCl3) d 166
(CONH), 157 (CarOCH3), 147 (CarNH2), 140 (CarCH2),
133 (CarHCCl), 128 (Car), 111 (CarCl and CarCONH),
98 (CarHCOCH3), 56 (OCH3), 53 (NHCH2Ph), 38
(CHNHCH2), 31 (CHNHCO), 15 (CH2). Anal. calcd
for C18H20ClN3O2.1/2H2O: C, 60.93; H, 5.97; N, 11.84.
Found: C, 61.03; H, 6.04; N, 11.86.
()-(cis)-4-Amino-N-[2-(N-benzyl-N-methylamino)-1-cy-
clopropyl]-5-chloro-2-methoxybenzamide (cis-3f). Fol-
lowing the procedure described for 3d, benzamide cis-3d
(0.2 g, 1 mmol) and 0.1 mL (1.5 mmol) of formaldehyde
(37% in methanol) gave 0.08 g (yield: 39%) of cis-3f by
ꢀ
1
recrystallization in diethyl ether, mp 157 C. H NMR
(CDCl3) d 8.2 (m, 1H, NH), 8.1 (s, 1H, HCCCl), 7.3 (m,
5H, Har), 6.2 (s, 1H, HCCOCH3), 4.4 (m, 2H, NH2), 3.9
(m, 2H, CH2N), 3.6 (s, 3H, OCH3), 3.4 (m, 1H,
CHNH), 2.2 (s, 3H, NCH3), 2.0 (m, 1H, CHN), 1.0 (m,
1H, CH2trans), 0.4 (m, 1H, CH2cis). Anal. calcd for
C19H22ClN3O2: C, 63.42; H, 6.16; N, 11.68. Found: C,
63.75; H, 6.33; N, 11.51.
Binding assays
Human dopamine D2 and D3 receptors. Chinese hamster
ovary (CHO) cells expressing human dopamine D3
(hD3) or D2 (short) receptors (hD2) were prepared as
described.22 Binding assays was carried out by incubating